As recently as 10 years go, nitric oxide was considered only a noxious gas that appeared in the exhaust of cars and in city smog, caused acid rain, and destroyed the ozone layer. This view changed tremendously in 1987 when nitric oxide was discovered to be produced in humans (Palmer, et al., Nature, 327:524-526, 1987; and Ignarro, L. J. et al., Proc. Natl. Acad Sci., 84:9265-9269, 1987). The status of nitric oxide was thus expanded from being an environmental threat to being a new pharmaceutical target of major medical importance (Carter, B. et al., Anaesth Intensive Care, 26(1):67-69, 1988; Moncada, S., Methods Find Exp. Clin Pharmicol, 19 Suppl A: 3-5, 1997; Vallace, P. and Moncada, S., J. Royal College Physicians, London 28: 209-219, 1994; and Romero, R., Hum Reprod. 13:248-250, 1998).
Nitric oxide is produced in the body by three different isoforms of the nitric oxide synthase (NOS) enzyme (see, for example, Singh, S. and Evans, T. W., Eur. Respir. J., 10:699-707, 1997). Neuronal NOS (nNOS) is found in neurons and plays a role in memory and pain perception. Endothelial NOS (eNOS) is found in vascular endothelial cells and plays an active role in vasodilatation and blood pressure regulation. Inducible NOS (iNOS) is expressed in astrocytes, microglial cells, neutrophils and in many other tissues in response to stimulation by inflammatory cytokines.
Like other biomediators, the level of nitric oxide in the body is tightly regulated. Both overproduction and underproduction of nitric oxide are associated with many diseases and conditions (see, for example, Moncada, S. and Higgs, E. A., FASEB J., 9:1319-1330, 1995). For example, excessive nitric oxide production is linked to many inflammatory diseases, including septic shock, hemorrhagic shock, allograft rejection, diabetes, arthritis, and neurogenerative diseases (Wolkow, P. P., Inflamm. Res. 47:152-166, 1998; Hierholzer, C. et al., J. Exp. Med., 187:917-928, 1998; Silkoff, P. E. et al., Am. J. Respir. Crit. Care Med., 157:1822-1828, 1988; Pieper, G. M., Hypertension, 31:1047-1060, 1998; Stichtenoth, D. O., Br. J. Rheumatol, 37:246-257, 1998; and Molina, J. A. et al., Drugs Aging, 12:251-259, 1998). On the other hand, insufficient nitric oxide production has been associated with human diseases, including impotence, atherosclerosis, essential hypertension, pre-ecalmpsia, and congestive heart failure (Hass, C. A. et al., Urology, 51:516-522, 1998; McHugh, J. et al., Am. J. Crit. Care, 7:131-140, 1998; Cardillo, C. et al., Circulation, 97:851-856, 1998; Buhimschi, I. A. et al., Hum. Reprod. Update, 4:25-42, 1998; Abassi, Z. et al., Am. J. Physiol., 274 (4 pt. 2):F766-F774, 1998).
A number of nitric oxide-releasing agents have been used to treat cardiovascular and pulmonary diseases associated with insufficient nitric oxide production (see, for example, Loskove, J. A. et al., Am. Heart J., 129:604-13, 1995). For example, organic nitrates, such as nitroglycerin and isosorbide dinitrates, have been widely used in the treatment of vascular heart diseases, such as the prevention of angina (see, for example, Torfgard, K. E. and Ahlner, J., Cardiovascular Drugs and Therapy, 8:701-717, 1994). However, such therapeutically administered nitric oxide-releasing agents can cause deleterious effects, many of which result from elevated levels of nitric oxide, when combined with one another or when combined with therapeutic compounds that interfere with metabolism of nitric oxide in the body.
Nitric oxide is a potent vasodilator (see, for example, Palmer in Arch. Surg. 128:396-401 (1993) and Radomski & Moncada in Thromb. Haemos. 70:36-41 (1993). For example, in blood, nitric oxide produced by the endothelium diffuses isotropically in all directions into adjacent tissues. As nitric oxide diffuses into the vascular smooth muscle, it binds to guanylate cyclase enzyme, which catalyzes the production of cGMP, inducing vasodilation (see, for example, Ignarro, L. J., Ann. Rev. Toxicol. 30:535-560 (1990); Moncada, S., Acta Physiol. Scand. 145:201-227 (1992); and Lowenstein and Snyder, Cell 70:705-707 (1992)). The overproduction of nitric oxide causes an extreme drop in blood pressure, resulting in insufficient tissue perfusion and organ failure.
Recently, patients taking sildenafil citrate (Viagra.RTM., Pfizer Laboratories) for treatment of male impotence have experienced side effects, such as headache, hypertension and dyspepsia, particularly when the drug is used in conjunction with organic nitrate drugs (see, for example, Goldstein, I. et al., N. Engl. J. Med., 338:1397-1404, 1998). Fatalities have been reported when Viagra.RTM. was used together with nitrate drugs, such as nitroglycerin.
There are additional situations in which a therapeutically administered source of nitric oxide can result in undesirable side effects. For example, the transfer of the gene encoding endothelial NOS into injured blood vessels reduces myointimal hyperplasia, as in restenosis, by providing a source of nitric oxide (see, for example, Janssens, S. et al., Circulation, 97:1274-1281, 1998). However, the continuing production of excessive nitric oxide from the NOS gene in the vessels can lead to nitric oxide-related oxidative damage in vivo.
Although therapeutically administered nitric oxide sources are beneficial in achieving therapeutic goals, such compounds can, in some cases, increase the level of nitric oxide above physiologically compatible levels in the subjects to whom they are administered. In other cases, the increased level of nitric oxide needed to achieve the increased level of nitric oxide may linger in the body longer than is therapeutically required. In addition, some subjects are treated with combinations of nitric oxide sources that may be administered separately to treat different conditions, but which, in combination, have an additive, or even synergistic, effect. In such cases, the patient may be unaware when a physiologically incompatible level of nitric oxide has been reached or when an otherwise therapeutic amount of a nitric oxide source becomes potentially dangerous due to combined effects of separately administered drugs.
It is known to use nitric oxide scavengers therapeutically to remove nitric oxide from the blood and/or tissues of subjects suffering from toxic levels of nitric oxide, such as those generated in many disease states (see, for example, Lai, C. S., U.S. Pat. Nos. 5,741,815; 5,756,540 and 5,757,532). Nitric oxide scavengers bind nitric oxide in vivo and the resulting complexes render nitric oxide harmless. The resulting complexes are eventually excreted in the urine of the host. Thus, nitric oxide scavengers are used to lower the level of nitric oxide in the subject, for example to a physiologically acceptable level.
However, new and better solutions are needed for the problem of controlling nitric oxide levels in subjects therapeutically administered sources of nitric oxide in treatment of disease states associated with depressed levels of endogenously produced nitric oxide. In particular, methods and compositions useful for administering nitric oxide scavengers to such subjects without compromising the therapeutic effect of the administered nitric oxide source are needed.